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Background COVID-19 related in-hospital venous thromboembolism (VTE) incidence is high but data reported vary significantly. Some studies show that up to half of the events are diagnosed early after admission. Objectives To study symptomatic VTE incidence in acute COVID-19 hospitalized patients and to describe timing of VTE diagnosis. Methods Multicenter cohort of 5966 patients hospitalized with acute COVID-19. Multicenter Registry of 844 hospitalized patients with acute COVID-19 and associated acute VTE. Results By the time of cohort data collection, 68 patients (1.14%) were still hospitalized, 19.8% had died, and 5.4% required ICU. During a median follow-up of 6 days (IQR, 4–12), 183 patients (3.07%; 95% CI, 2.64–3.55) presented a symptomatic VTE event. The cumulative incidences of VTE at 7, 14 and 21 days in wards [2.3% (95% CI, 1.9–2.7), 3.6% (95% CI, 3.0–4.3), and 4.3% (95% CI, 3.5–5.1)] were similar to the ones reported in ICU [2.2% (95% CI, 1.0–4.4), 2.9% (95% CI, 1.5–5.3), and 4.1% (95% CI, 2.2–6.8)], but at 30 and 60 days were higher in ICU [6.9% (95% CI, 4.2–10.5), and 12.8% (95% CI, 8.1–18.5)] than in wards. Eighty-eight VTE events (48%) were diagnosed early, within 48 h of admission. VTE was not associated with death (HR, 0.79; 95% CI, 0.55–1.12). Conclusions Incidence of symptomatic VTE in our COVID-19 cohort is consistent with that of other real-life studies recently published. Early VTE events are, along with COVID-19, the reason for admission rather than an in-hospital complication.

Socially responsible behaviors (SRBs) in the workplace and in life more generally can positively contribute to the well-being of society and the environment at large. SRBs can benefit many people, especially in extreme contexts. In this article, we report on an investigation of the relationship between employees’ proactive personality and their engagement in two types of SRBs: societal behaviors and sustainability-oriented behaviors. Furthermore, we test the moderation effect of perceived danger (contextual factor) on these relationships. To assess the hypotheses, three studies were conducted in different countries: (1) Iran, which is under intense economic sanctions; (2) Peru, which has dealt with severe restrictions during the COVID-19 pandemic; and (3) Afghanistan, which is involved in a long-standing internal war. We tested the direct relationship between proactive personality and SRBs by using survey-based data from 292 employees in Iran and 306 employees in Peru. The moderation effect of perceived danger (contextual factor) is assessed using data from 172 employees in Afghanistan. Accordingly, we found a consistent pattern of relationships between employees’ proactive personalities and their involvement in both societal behaviors and sustainability-oriented behaviors in Iran and Peru. Interstingly, the results from Afghanistan revealed that employees with a proactive personality engaged more in societal behaviors under threatening and stressful situations.

Video game localisation, a field highly impacted by the lack of visual environment and text linearity, forces translators to create inclusive solutions in terms of gender to overcome the hurdles created by variables. This paper will introduce the specificities of this sector and present an analysis of some of those techniques extracted from parallel corpora compiled from video games that include female, transgender, non-binary, and non-sexualised characters. LE GENRE DANS LES JEUX VIDÉO : LA CRÉATIVITÉ POUR L'INCLUSIVITÉ La localisation de jeux vidéo, un domaine très impacté par l’absence d’accès au jeu ainsi que par le manque de linéarité textuelle, oblige les traducteurs à trouver des solutions inclusives pour faire face aux problèmes créés par les variables. Cet article se propose d’introduire les caractéristiques du secteur ainsi que de présenter l’analyse des techniques extraites des corpus parallèles compilés à partir des jeux ayant des personnages féminins, transgenres, non-binaires, et non-sexualisés., {"references":["UREN, E., HOWARD, R., & PERINOTTI, T. Software Internationalization and Localization: An Introduction. 1993. ISBN 10: 0442014988","DUNNE, K.J. Localization and the (R)evolution of Translation. En: S. BERMANN, C. PORTER ed. A Companion to Translation Studies. John Wiley & Sons, Ltd. 2014, p. 147-162.","PYM, A. The Moving Text: Localization, translation, and distribution. John Benjamins Publishing Company, 2004. ISBN 9789027295828","BERNAL- MERINO M.A. The Localisation of Video Games. Translation Studies Unit Imperial College, London, 2013, p. 67.","MANGIRON HEVIA, C. & O'HAGAN, M. Game Localization: Translating for the global digital entertainment industry. John Benjamins, 2013. ISBN 9789027271860","BERNAL- MERINO M.A. On the Translation of Video Games. In: JoSTrans, The Journal of Specialised Translation. 2006. No. 6. p. 22-26. ISNN 9781315752334","RIVAS GINEL, M.I. Ergonomics of Tools Usage for Video Game Localisation: A User Survey. In: >\tCritic. 2021. No.2. p. 27 – 57. ISBN-13: 979-8453471812","TECHOUEYRES, P. LocJam Masterclass. 2020. min. 27:11 – 28:47 (consulted the 13.03.2022) available at https://www.youtube.com/watch?v=YAbl257stHo&ab_channel=LocalisationDijon","HERITAGE, F. Language, Gender and Videogames. Switzerland: Palgrave Macmillan, 2021. ISBN: 978-3-030-74398-7.","RIVAS GINEL, M.I. & THEROINE, S. Machine Translation and Gender biases in video game localisation: a corpus-based analysis In: Colloque interdisciplinaire « Vers une robotique du traduire ? », 30 sept. – 1er oct. 2021. Strasbourg. ⟨hal-03540605⟩","GOTTLIEB, H. A New University Discipline. In: C. DOLLERUP, & A. LODDEGAARD, ed. Teaching Translation and Interpreting: Training, talent and experience. John Benjamins Publishing Company. 1992. DOI: 10.1075/z.56.26got","HADDAD, R. Manuel d'écriture inclusive. 2019. (consulted the 14.03.2022) available at https://www.motscles.net/ecriture-inclusive","CREMIER, L. Rédaction inclusive, féminisation et approches créatives du genre grammatical en français: comment traduire le genre. In : 4ème conférence du Comité pancanadien de terminologie. Équité, diversité et inclusion : l'importance de la terminologie., 27 janvier 2022. Online. UQAM, IREF, 2022.","ALPHERATZ. Grammaire du français inclusif: littérature, philologie, linguistique. Ed: Vent solars, 2018. ISBN: 9782955211861"]}

Thrombocytopenia has been identified as a common complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the general population. In an attempt to determine the impact of coronavirus disease 2019 (COVID-19) in patients with immune thrombocytopenia (ITP), a retrospective single-centre study was performed. Thrombocytosis was observed in patients with chronic ITP after SARS-CoV-2 infection, frequently needing treatment adjustment or even discontinuation of therapy. Relapses and newly diagnosed cases showed a fast response after initial treatment compared to ITP. Reduced immune activity due to lymphopenia during COVID-19 could explain this paradoxical effect, although further studies are needed.

INTRODUCTION: We present the first registry of patients with congenital bleeding disorders and COVID-19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID-19, the course of the disease if it occurs and the psychosocial and occupational impact on this population. METHODS: We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data. RESULTS: Forty-two patients presented symptoms suggestive of infection by COVID-19, and in six cases, the disease was confirmed by RT-PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID-19 in two patients on prophylaxis with non-factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person. CONCLUSIONS: Patients with congenital bleeding disorders infected with SARS-CoV-2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID-19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.

It is important to investigate which factors are associated with the development of arthropathy in people with mild haemophilia (PWMH), in order to prevent it and to limit its effect on function and quality of life.To examine the risk factors associated with arthropathy and to predict its presence and degree of involvement in our PWMH population.This was an observational, cross-sectional cohort study of 85 PWMH under follow-up in our centre. Patient variables (age, body mass index, haemophilia type, genetic mutations, baseline factor levels, age at diagnosis, history of inhibitor, level of physical activity and years of practice, history of haemarthrosis and muscle haematoma) were analysed and related to the presence or absence of arthropathy and the degree of arthropathy (measured with HJHS and HEAD-US). Multivariable models were performed.Some 36.5% of PWMH had arthropathy. The variables that showed an independent association with the presence of arthropathy were patient age (median 42 years) and clotting factor levels (median 10.5 IU/dL). The risk of developing arthropathy increased by 7.9% for each additional year of age and decreased by 7.7% for each 1 IU/dL increase in clotting factor. When arthropathy developed, its degree of involvement might have been influenced by the type of physical activity performed.Patient age and factor levels appear to be the most determinant risk factors associated with the development of arthropathy in mild haemophilia. Monitoring joint health is desirable in this patient population. In patients with arthropathy, physical activities with a low risk of bleeding are the most recommended.

Introducción: La hemofilia es una enfermedad rara, por lo que su abordaje en Urgencias puede suponer un reto para los pediatras. Objetivos: Describir la frecuencia y motivos de consulta de los niños hemofílicos en Urgencias. Material y métodos: Estudio retrospectivo longitudinal realizado en Urgencias Pediátricas de un hospital de tercer nivel. Se incluyeron hemofílicos A y B, desde el nacimiento hasta los 16 años, que consultaron por cualquier motivo durante 6 años (2011-2016). Se analizaron: edad, tipo y gravedad de hemofilia, motivo de consulta, profilaxis domiciliaria frente a sangrados, pruebas complementarias, diagnóstico establecido, tratamiento y número de visitas a Urgencias. Resultados: Se analizaron 116 varones con un total de 604 visitas. La media de edad fue de 5,5 años y la mediana de 5,3. De ellos, 101 pacientes eran hemofílicos A (38 leves, 4 moderados, 59 graves) y 15 hemofílicos B (9 leves, 3 moderados, 3 graves). Los principales motivos de consulta (clasificados en triaje) fueron: problema musculoesquelético/traumático o sangrado (66,7%), causas no relacionadas con hemofilia (29%), sospecha de infección de catéter central (2,8%) y administración rutinaria de factor (1,5%). Se realizaron pruebas complementarias en 335 visitas (55,5%). Del total, 317 consultas (52,5%) requirieron factor; 103 episodios (17,1%) precisaron ingreso, cuyos principales motivos fueron: traumatismo craneoencefálico (35,9%), infección de catéter venoso central (13,6%), hemartrosis (8,7%), hematoma muscular (6,8%) y hematuria (5,8%). Conclusión: Los pacientes consultaron por causas habituales de la edad pediátrica, pero también lo hicieron por motivos específicos de su enfermedad; lo más frecuente fue el problema musculoesquelético/traumático o sangrado. El Servicio de Urgencias es un componente indispensable en su atención, Introduction: Haemophilia is a rare disease and its management can pose a challenge to Emergency Department paediatricians. Aim: To describe the frequency and reasons for consultation by haemophilic children in the ED. Materials and methods: Longitudinal retrospective study was conducted in a paediatric Emergency Department of a tertiary care hospital. The study included haemophiliacs A and B, ages 0 to 16 years old, and who had consulted the Emergency Department for whatever reason over a span of 6 years (2011-2016). The data analysed include: age, type and severity of haemophilia, reason for query, prophylactic status, complementary examinations, established diagnosis, treatment, and number of visits to the Emergency Department. Results: The analysis included 116 males with a total of 604 Emergency Department visits. The mean age was 5.5 years, and the median age was 5.3 years. A total of 101 patients were categorised as haemophiliac A (38 mild, 4 moderate, 59 severe), and 15 as haemophiliac B (9 mild, 3 moderate, 3 severe). The main reasons for initial Emergency Department visits (ranked by triage) were: musculoskeletal problems/injury or bleeding (66.7%), causes unrelated to haemophilia (29%), suspected central venous catheter related infection (2.8%), and routine clotting factor infusion (1.5%). Additional tests were conducted during 335 visits (55.5%). Factor replacement was undertaken in 317 visits (52.5%). A total of 103 episodes (17.1%) required hospital admission, due to: head trauma (35.9%), central venous catheter -related infection (13.6%), haemarthrosis (8.7%), muscle haematoma (6.8%), and haematuria (5.8%). Conclusion: Haemophilic patients went to the Emergency Department for common paediatric causes, but also requested consultation on specific problems related to haemophilia, with musculoskeletal problems/injury or bleeding being the main issues. The paediatric Emergency Department is an indispensable component of haemophilia care

The treatment goal for patients with immune thrombocytopaenia (ITP) is to raise platelet counts to levels that minimize or stop bleeding. Thrombopoietin receptor agonists (TPO-RAs) have been successfully and extensively employed as second-line therapy for ITP. However, TPO-RAs have a small but significant increase in the risk of thrombosis. The aim of this study was to elucidate the mechanisms involved in the pro-coagulant effect of TPO-RAs to take them into account when considering their use in ITP patients with concomitant diseases/conditions that might increase risk of suffering thrombotic events. Eighty-two patients with chronic primary ITP (40 untreated and 42 undergoing TPO-RA therapy) and 112 healthy individuals were recruited. The patients with ITP undergoing TPO-RA therapy presented a pro-coagulant profile due to the formation of a more fibrinolysis-resistant clot because of increased plasminogen activator inhibitor-1 (PAI-1) levels. Increase in platelet content of PAI-1 might be the result of the effect of TPO-RA during megakaryopoiesis, as suggested by experiments performed in MEG-01 cells. Moreover, patients under TPO-RA treatment presented an enhanced pro-coagulant activity associated with microparticles and an increased platelet apoptosis that causes a higher exposure of phosphatidylserine and, consequently, a larger surface for the binding of the prothrombinase complex.

Summary • Polyamine biosynthesis inhibitors were used to study polyamine metabolism during the germination of Sclerotinia sclerotiorum ascospores, and to evaluate the potential of polyamine biosynthesis inhibition for the control of ascospore-borne diseases in plants. • The effects of inhibitors on ascospore germination, free polyamine levels, ornithine decarboxylase activity and development of disease symptoms on tobacco (Nicotiana tabacum) leaf discs inoculated with ascospores were determined. • α-Difluoromethylornithine inhibited ornithine decarboxylase and decreased free spermidine levels, but had no effect on ascospore germination. Both, the spermidine synthase inhibitor cyclohexylamine and the S-adenosyl-methionine decarboxylase inhibitor methylglyoxal bis-[guanyl hydrazone] decreased free spermidine levels, but only the latter inhibited ascospore germination, at concentrations of 5 mm or higher. Lesion development on leaf discs was reduced by cyclohexylamine and methylglyoxal bis-[guanyl hydrazone], but not by α-difluoromethylornithine. In the absence of inhibitors, dormant ascospores contained higher polyamine levels than mycelium. • Ascospore germination did not depend on ornithine decarboxylase activity and inhibitors of this enzyme will probably have a limited potential for the control of ascospore–borne plant diseases. On the contrary, spermidine synthase and S-adenosyl-methionine decarboxylase could be more suitable targets for fungicidal action. The relative insensitivity of ascospore germination to polyamine biosynthesis inhibitors may be caused by their high polyamine content.

Loss of sialic acid from the carbohydrate side chains of platelet glycoproteins can affect platelet clearance, a proposed mechanism involved in the etiopathogenesis of immune thrombocy-topaenia (ITP). We aimed to assess whether changes in platelet glycosylation in patients with ITP affected platelet counts, function, and apoptosis. This observational, prospective, and transversal study included 82 patients with chronic primary ITP and 115 healthy controls. We measured platelet activation markers and assayed platelet glycosylation and caspase activity, analysing samples using flow cytometry. Platelets from patients with ITP with a platelet count, This research was funded by FIS-Fondos FEDER PI19/00631, FIS-Fondos FEDER PI19/00772 and Platelet Disorder Support Association

Background and Objectives: The aim of this study was to determine the impact of the COVID-19 pandemic on the lives of patients with immune thrombocytopaenia (ITP) treated at our hospital. Materials and Methods: The study was conducted in the Community of Madrid, which has the highest number of COVID-19 cases in Spain. We included 143 adult patients with ITP (130 with chronic ITP, 8 with persistent ITP, and 5 with newly diagnosed ITP). We conducted a telephone survey to collect the data and created a registry. Materials and Methods: Overall, 24 patients presented symptoms suggestive of COVID-19, which was confirmed by RT-PCR in 8 cases. The cumulative incidence of confirmed SARS-CoV-2 infection was higher in the patients with ITP than in the Madrid population. There were no differences in the disease incidence or clinical course of infection in the patients treated with immunosuppressants. Almost all of the patients reported adherence to the prescribed treatment, although 49.2% of the hospital visits were either cancelled or postponed, 17.2% because of the patients’ fear of coming to the centre. Nearly half of the cohort was considered vulnerable, and 17% had been granted a dependency or disability benefit. Conclusions: COVID-19 had a major impact on the psychosocial, occupational, and quality of care of patients with ITP., This study was supported by FIS-Fondos FEDER PI19/00631 and PI19/00772 and by the Platelet Disorder Support Association

Acquired haemophilia A (AHA) is a rare severe bleeding disorder resulting from the production of autoantibodies directed against coagulation factor VIII. At presentation, bleeding events can be severe, and an early diagnosis and treatment are of major importance. The current study aims to analyse the treated patients who have been diagnosed with AHA for a better understanding of our population and treatment outcome. We conducted a retrospective study with 26 patients who had been diagnosed with AHA and who were treated in our hospital between January 2006 and January 2021. The patients ranged in age from 30 to 85 years old: 46.10% were men, 46.10% had no known underlying condition, 27% had an underlying malignancy, 7.60% presented with other diseases: psoriatic arthritis and Paget’s disease, and 19.30% presented with AHA during puerperium. All of the patients had bleeding events and were treated with bypass agents for this as well as with immunosuppressive therapy to eradicate the inhibitor. A total of 53.80% of the patients had major bleeding. Sixty-nine percent of the patients achieved complete remission, but 26.90% died during the follow-up, although bleeding was not the cause of death in any of these cases. Our observations underline the importance of clinical suspicion and early referral to centres with experience and laboratory facilities for managing AHA.

We describe the case of a patient with severe hemophilia A who underwent major orthopedic surgery managed postoperatively by telemedicine (TM). The case is a splendid example of the implementation of TM and good collaboration between a Comprehensive Hemophilia Treatment Center (CHTC) and a local hospital.

Severe acute respiratory syndrome coronavirus 2 community-wide transmission declined in Spain by early May 2020, being replaced by outbreaks and sporadic cases. From mid-June to 2 August, excluding single household outbreaks, 673 outbreaks were notified nationally, 551 active (>6,200 cases) at the time. More than half of these outbreaks and cases coincided with: (i) social (family/friends’ gatherings or leisure venues) and (ii) occupational (mainly involving workers in vulnerable conditions) settings. Control measures were accordingly applied.

In times of crisis, continuous adaptation is necessary. Communication between all members of a research team is key to adapting the development of clinical trials to the context of the epidemiological crisis of coronavirus. We are accustomed to performing day‐to‐day tasks to fulfil protocol requirements with precision. To this end, we typically have had protocol‐guided face‐to‐face visits and we have followed a detailed sequenced procedure during each visit.

The central objective of proposing intervention strategies that incorporate prevention and coping measures with emphasis on environmental education aimed at the sustainable development of the municipality of Bom Jesus da Lapa, located in the northwest of the State of Bahia, in the Northeast of Brazil, where rivers, riparian forests and land for agriculture are unprotected. It is necessary to identify the socioeconomic conditions of the farmers and inhabitants of the rivers who live in the rural area of the municipality, registered in the associations investigated, to guide them based on sustainable production. The most relevant results have shown that a more complex and coordinated work, of great proportions, is necessary in order to offer the inhabitants of the region an environmental education of quality, which really helps the inhabitants of the area to produce and, at the same time, preserve the natural resources (flora and fauna) of the region. Understanding sustainable development requires discussing the social mediations that underlie the very meaning of development and the meaning of the environmental crisis. This is a dual articulation of ideas, which involves a theoretical tension and a conceptual strength, present in contemporary capitalism. For there to be sustainable development, there must be environmental awareness of society as a whole. Both schools and educators have to play their part, so that sustainable development can be achieved. It is believed that an effective tool for environmental awareness is made through formal education, putting into practice. O objetivo central deste escrito é o de propor estratégias de intervenção que incorporem medidas de prevenção e enfrentamento com ênfase na educação ambiental, voltada para o desenvolvimento sustentável do município de Bom Jesus da Lapa, localizado no noroeste do estado da Bahia, no Nordeste do Brasil, onde rios, florestas ripícolas e terras destinadas à agricultura estão desprotegidos. É necessário identificar as condições socioeconômicas dos agricultores e habitantes dos rios que vivem na área rural do município, registrados nas associações investigadas, para orientá-los com base na produção sustentável. Os resultados mais relevantes demonstraram que um trabalho mais complexo e coordenado, de grandes proporções, é necessário, para que assim se possa oferecer aos habitantes da região uma educação ambiental de qualidade, que realmente os ajude a produzir e, ao mesmo tempo, preservar os recursos naturais (flora e fauna) da região. Compreender o desenvolvimento sustentável exige discutir as mediações sociais que fundamentam o próprio significado de desenvolvimento e o sentido da crise ambiental. Trata-se de uma dual articulação de ideias, que envolve uma tensão teórica e uma fortaleza conceitual presente no capitalismo contemporâneo. Assim, para que haja o desenvolvimento sustentável, deve haver consciência ambiental da sociedade como um todo. Logo, tanto as escolas como os educadores têm de fazer seu papel, para que se atinja o desenvolvimento sustentável. Dessa forma, acredita-se que uma eficaz ferramenta para a consciência ambiental se faz através do ensino formal, colocando em prática atitudes ecologicamente corretas para o bem-estar das populações. El objetivo central de este trabajo es proponer estrategias de intervención que incorporen medidas de prevención y enfrentamiento con énfasis en la educación ambiental orientada al desarrollo sostenible del municipio de Bom Jesus da Lapa, ubicado en el noroeste del estado de Bahía, en el Nordeste de Brasil, donde ríos, bosques ripícolas y las tierras destinadas a la agricultura se encuentran desprotegidos. Es necesario identificar las condiciones socioeconómicas de los agricultores y habitantes de los ríos que viven en el área rural del municipio, registrados en las asociaciones investigadas, para orientarlos con base en la producción sostenible. Los resultados más relevantes demostraron que un trabajo más complejo y coordinado, de grandes proporciones, es necesario, para que así se 105 pueda ofrecer a los habitantes de la región una educación ambiental de calidad, que realmente les ayude a producir y, al mismo tiempo, preservar los recursos naturales (flora y fauna) de la región. Comprender el desarrollo sostenible exige discutir las mediaciones sociales que fundamentan el propio significado del desarrollo y el sentido de la crisis ambiental. Se trata de una doble articulación de ideas, que implica una tensión teórica y una fortaleza conceptual, presente en el capitalismo contemporáneo. Así que, para que haya un desarrollo sostenible, hay que tener conciencia ambiental de la sociedad como un todo. Tanto las escuelas como los educadores tienen que hacer su papel, para que así se alcance el desarrollo sostenible. De esa manera, se cree que una eficaz herramienta para la conciencia ambiental se hace a través de la enseñanza formal, poniendo en práctica actitudes ecológicamente correctas para el bienestar de las poblaciones.

Etiopathogenesis of myelodysplastic syndrome (MDS) might cause per se an anomalous haemostasis that can be even more deteriorated by thrombocytopaenia. So, evaluation of haemostasis in patients with MDS rises as a necessity.This work aimed to characterize haemostasis in non-bleeder MDS patients with a platelet count similar to healthy controls to establish differences between the two groups not related to thrombocytopaenia.Thromboelastometry in samples from MDS patients suggested the existence of at least two antagonistic processes: one of them giving a hypocoagulable pattern (prolonged clotting time and lower α angle) and another conferring a procoagulant profile (decreased fibrinolysis). Hypocoagulable state might be due to a decreased ability of platelets to be stimulated and to the presence in plasma of a factor/s that prolonged the time to initiate thrombin generation. This factor/s might be antibodies as this effect was observed in samples from MDS patients with an associated autoimmune-inflammatory condition.Otherwise, hypercoagulable state seemed to rely on an increased presence of red cell- and monocyte-derived microparticles and to the increased exposure of phosphatidylserine that served as scaffold for binding of coagulation factors.We concluded that haemostasis in MDS patients is a complex process influenced by more factors than platelet count.

Background: Primary immune thrombocytopenia (ITP) is a megakaryocytic (MK)/platelet-specific autoimmune disorder characterized by platelet count It is widely accepted the involvement of platelet autoantibodies on deterioration of platelets from patients with ITP. Moreover, an enhanced activity of neuraminidase may also reduce sialic acid from glycoside residues on platelet surface, especially from the highly glycosylated von Willebrand factor (vWF) receptor. Because controversial results regarding the functionality of platelets from ITP patients can be found in literature, we aimed to determine platelet ability to be stimulated by agonists. Moreover, we aimed to determine the way anti-platelet auto- antibodies (abs) and neuraminidase activity may affect the function of platelets derived from MKs of healthy controls. Methods: This observational, prospective and transversal study included 42 patients with chronic primary ITP and 55 healthy controls. Platelet fibrinogen and vWF receptors and activation markers (PAC1 binding to activated fibrinogen receptor and exposure of P-selectin after agonists treatment), were evaluated by flow cytometry. Presence of Antibodies (abs) against platelet's glycoproteins in ITP serum was analysed with a Luminex based assay (LifecodesPak Lx). Neuraminidase (NEU) activity in serum was determined with the substrate 20-(4-methylumbelliferyl)-a-D-N-(MUNANA). Human CD34 + cell-enriched population was obtained with CliniMACS (MiltenyiBiotec) from G-CSF mobilized peripheral blood of a healthy donor. For MK differentiation, CD34 + cells were cultured 12 days in StemSpan™ Serum-Free Expansion Medium II (SFEM II) with 50ng/ml of recombinant human thrompoietin. Then, 10% of serum from healthy controls (4) or ITP patients (4) were added to the culture of mature MKs and incubated for 3 days. Phenotypic analysis of MKs and culture derived-platelets was carried out using abs against CD34, CD41, CD42a and CD42b.Platelet-like particles were considered as CD41-positive events with a size (FSC) and granularity (SSC) scatter properties similar to blood platelets. Culture-derived platelets were stimulated with 100 µM TRAP and 10 µM ADP and activation markers were analyzed by flow cytometry. Results: Expression of fibrinogen receptor on platelets from ITP patients were similar to those from healthy controls but showed a reduced capacity to be activated. Impairment in platelet degranulation measured as exposition of P-selectin after agonist's stimulation was also observed in platelets from these patients (Figure 1). Of note, surface content of CD42b subunit of vWF receptor was reduced (Figure 1). To determine whether diminished platelet function might be due to a plasma component, we induced platelet production from MK of healthy controls as referred in Methods. Abs against platelets and neuraminidase activity were determined in serum samples. Serum from 4 healthy controls or from 4 ITP patients (1 with anti-CD42b, 1 with anti-GPIa-IIa and 2 with undetectable abs) were added to MKs culture. No differences existed in MK differentiation and platelet production between MKs incubated with serum from healthy controls or from ITP patients, but similarly as observed in platelets from ITP patients, MK-derived platelets had an impaired ability to be activated (Table 1). Platelets derived from MKs incubated with ITP serum with anti-platelet abs had also a diminished exposure of CD42b (73±8% of controls). Moreover, neuraminidase content of these samples was slightly higher than that from ITP samples without abs (130 vs 100 % of controls). Conclusion: Platelets from ITP patients had a diminished ability to be stimulated. In vitro study showed that megakaryopoiesis was normal in presence of ITP serum, but released platelets had a lower ability to be activated. Involvement of abs in this effect cannot be ruled out despite we detected abs only in 2 of the tested sera because efficiency of method to detect these abs is ~ 50%. On the other hand, reduced levels of CD42b might be due to the increased activity of neuraminidase. Reduction of sialic acid from CD42b might initiate its metalloproteinase-mediated cleavage or change affinity of the ab used for its detection. Research funded by ISCIII-Fondos FEDER PI19/00772 and Platelet Disorder Support Association Figure 1 Figure 1. Disclosures Alvarez Román: Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding. García Barcenilla: Roche: Speakers Bureau; Takeda: Speakers Bureau; Bayer: Speakers Bureau; SOBI: Speakers Bureau. Canales: Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Incyte: Consultancy; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; iQone: Honoraria; Sandoz: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Jiménez-Yuste: Grifols: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Butta: Novo-Nordisk: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Roche: Speakers Bureau; CSL-Behring: Research Funding.

Introduction: The management of Factor (F) VII deficiency is complex due to the lack of a clear correlation between FVII levels and the bleeding manifestations of the patients, with a variety of responses to the treatments. Additionally,the presence of FVII inhibitors may also occur. Thus, it is essential to be able to monitoring the hemostatic profile and the effect of the different therapies in each patient individually. Our aim was to perform a personalized analysis of the coagulation status of patients with FVII deficiency and to evaluate their response to new potential therapies using five different coagulation tests. Methods: Six patients were included (clinical data in Table-1):4 with bleeding symptoms on prophylaxis with recombinant activated FVII (rFVIIa), one of them with FVII inhibitors; and 2 untreated patients without bleeding episodes. Blood samples obtained from patients on prophylaxis were collected predose. Prothrombine time (PT) and activated partial thromboplastin time (aPTT)were tested using HemosIL ® RecombiPlasTin 2G, and SynthASil respectively. Rotational Thromboelastometry (ROTEM ®) was performed for monitoring the clot formation using blood with corn trypsin inhibitor (CTI) to inhibit contact activation and a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using platelet poor plasma (PPP) obtained from blood with CTI and activated with only 1 pM TF plus phospholipids (PPP-Low ®, Stago). The plasmin generation (PG) was measured in citrated PPP using a comercial kit (Synapse). The total thrombus-formation analysis system (T-TAS ®, Zacros) was conducted by loading CTI blood samples in AR-chips coated with collagen and thromboplastin for assessing thrombus formation mediated by the activation of the coagulation under flow conditions (High shear). The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Effects of ex vivo spiking doses of factor replacement (rFVIIa) or non-factor replacement treatments (anti-TFPI, clone mAb2021, Creative Biolabs) were tested. Results: aPTT values remained normal in all patients. FVII deficiency significantly affected PT and patients with more severe bleeding phenotype (patient #1, 2, 3, and 4) showed much longer PT values. Similarly, ROTEM and T-TAS assays showed that FVII deficiency only caused an important delayed clotting time (CT) and very anomalous thrombus formation (AUC) in patients with severe bleeding symptoms.More prolonged lag time (LT) and an important decrease in the peak of thrombin and plasmin generation was also observed in the same patients (#1, 2, 3, and 4). Patient #1 with FVII inhibitors presented a more affected hemostatic profile according to all the coagulation parameters obtained with the five different assays. In contrast, the patients #4 and #5 with absence of bleeding complications showed most of these values within the normal reference range obtained from healthy controls. Concentrations of 1µg/ml (equivalent to 90 μg/kg) of the factor-replacement treatment rFVIIa, showed the normalization of the PT, the clotting time (CT), and the restoration of the thrombin and plasmin generation, and the regularization of the coagulation-dependent thrombus formation in all the patients. In vitro spiking with anti-TFPI (400-800 ng/ml), an alternative non-factor replacement treatment,corrected the thrombus formation (AUC) defects under high shear flow observed in the patients, and produced a significant reduction of CT and LT, and increments of thrombin generation although less effectively than the factor replacement therapy. Conclusions: All the global tests, performed with the described conditions in this study, were sensitive enough to show an abnormal hemostatic profile in the FVII-deficient patients with worst clinical symptoms, validating their use to monitor the risk of bleeding events and the responses to different treatments in this deficiency. These assays may allow to monitoring more personalized treatments to these patients. The results also pointed to the possibility that inhibition of TFPI might be useful for treatment of patients with FVII deficiency, opening the idea of its usage especially as an alternative therapy for patients with inhibitors. Research funded by ISCIII-Fondos FEDER PI19/00772 and PI19/00631 Figure 1 Figure 1. Disclosures Alvarez Román: Pfizer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. García Barcenilla: Roche: Speakers Bureau; Takeda: Speakers Bureau; SOBI: Speakers Bureau; Bayer: Speakers Bureau. Canales: Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Incyte: Consultancy; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; iQone: Honoraria; Sandoz: Honoraria, Speakers Bureau; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria. Butta: CSL-Behring: Research Funding; Roche: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novo-Nordisk: Speakers Bureau. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.